Sleep and APOE-ε4 have a synergistic effect on plasma biomarkers and longitudinal cognitive decline in older adults

Abstract

Background: Sleep disorders are prevalent among patients with Alzheimer's disease (AD), and the APOE ε4 genotype is a key genetic risk factor for sporadic AD. However, the combined effect of the genotype and sleep disorders on cognitive decline remains uncertain.

Methods: A total of 972 participants were drawn from the SILCODE cohort, comprising 655 without the ε4 allele (APOE-) and 317 with ε4 allele (APOE+). Data were collected, including neuropsychological assessments, sleep measurements, plasma biomarkers, and PET imaging. A Sleep Composite Index (SCI) was created, categorizing participants into high risk (Sleep+) and low risk (Sleep-).

Results: Significant predictions of dementia risk associated with plasma p-tau181, neurofilament light chain (NfL), and SCI. Individuals with both Sleep+ and APOE+ had a higher risk of dementia compared to those with Sleep-. The Sleep+/APOE+ group had higher plasma NfL levels than the Sleep-/APOE- group. Similar trends emerged in plasma NfL levels among the Aβ PET-positive subgroup. Plasma NfL levels explained 23% of the relationship between SCI and cognitive impairment.

Conclusion: Our study highlights sleep disorder was associated with cognitive decline, with plasma NfL playing a partial mediating role. These findings explain how sleep disorders affect cognitive function and emphasize the importance of healthy sleep for older adults.

Keywords: APOE ε4; Alzheimer's disease; biomarkers; discrimination; sleep.

FIGURE 1

Estimation of various biomarkers on future conversion to dementia. GFAP, glial fibrillary acidic protein; HR, hazard ratio; NfL, neurofilament light chain; SCI, Sleep Composite Index.

FIGURE 2

Relationship between SCI and plasma biomarkers. (A–D) Group differences in plasma biomarkers grouped by SCI score; and (E–H) relationship between plasma biomarkers and SCI scores in Sleep+ group. SCI, Sleep Composite Index; Sleep +, high‐risk group; Sleep−, low‐risk group.

FIGURE 3

SCI and APOE ε4 genotype on future dementia risk and plasma biomarkers level. (A–C) Estimation of SCI and APOE ε4 genotype on future dementia risk. (A) Whole group, (B) Aβ PET‐positive subgroup, (C) Aβ PET‐negative subgroup; (D–O) SCI and APOE ε4 genotype on plasma biomarkers level; (D–G) whole group; (H–K) Aβ PET‐positive subgroup; (L–O) Aβ PET‐negative subgroup.

FIGURE 4

Mediation path diagram showing plasma NfL as a potential mediator between SCI (independent variable) and CI dependent variable (A). Mediation path diagram showing SCI as a potential mediator between GDS (independent variable) and plasma Aβ42/40 (dependent variable, B). CI, cognitive impairment; GDS, Geriatric Depression Scale; NfL, neurofilament light chain; SCI, Sleep Composite Index.